药学学报, 2015, 50(7): 808-813
引用本文:
王根柱, 戚欣, 李静. 真核延伸因子2激酶与肿瘤[J]. 药学学报, 2015, 50(7): 808-813.
WANG Gen-zhu, QI Xin, LI Jing. Eukaryotic elongation factor 2 kinase and cancer[J]. Acta Pharmaceutica Sinica, 2015, 50(7): 808-813.

真核延伸因子2激酶与肿瘤
王根柱, 戚欣, 李静
中国海洋大学医药学院, 海洋药物教育部重点实验室, 山东 青岛 266003
摘要:
真核延伸因子2激酶 (eEF2K) 是一种Ca2+/CaM依赖性蛋白激酶, eEF2是其已知的唯一底物。eEF2K催化eEF2的Thr56位点发生磷酸化, 导致降低eEF2与核糖体的结合能力进而抑制肽链延伸。现已发现, eEF2K在多种肿瘤细胞中高表达或高度活化, 参与肿瘤进程的调控, 因此eEF2K可能是一个潜在的肿瘤治疗靶点。本文就eEF2K的结构、功能、与肿瘤的关系及其抑制剂的研究进展进行综述。
关键词:    真核延长因子2激酶      肿瘤      抑制剂     
Eukaryotic elongation factor 2 kinase and cancer
WANG Gen-zhu, QI Xin, LI Jing
Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
Abstract:
Eukaryotic elongation factor 2 kinase (eEF2K) is well known as a Ca2+/calmodulin (CaM)-dependent kinase. eEF2K catalyzes the phosphorylation of eEF2 and subsequently inactivates eEF2 by impairing its ability to bind to the ribosome, thereby negatively modulates protein synthesis. The high expression of eEF2K has been found recently in several types of malignancies. As participating in the progress of tumor, eEF2K emerges a potential target for future cancer therapy. The relationship between eEF2K and tumor, and the latest progress of eEF2K inhibitors were summarized in this article.
Key words:    eukaryotic elongation factor 2 kinase    cancer    inhibitor   
收稿日期: 2015-01-19
基金项目: 山东省自然科学基金资助项目 (ZR2012CM005); 山东省自然科学基金青年基金资助项目 (ZR2013HQ066).
通讯作者: 李静
Email: ljlilac@163.com
相关功能
PDF(1369KB) Free
打印本文
0
作者相关文章
王根柱  在本刊中的所有文章
戚欣  在本刊中的所有文章
李静  在本刊中的所有文章

参考文献:
[1] Nairn AC, Bhagat B, Palfrey HC. Identification of calmodulin-dependent protein kinase III and its major Mr 100 000 substrate in mammalian tissues [J]. Proc Natl Acad Sci USA, 1985, 82: 7939-7943.
[2] Chafouleas JG, Pardue RL, Brinkley BR, et al. Regulation of intracellular levels of calmodulin and tubulin in normal and transformed cells [J]. Proc Natl Acad Sci USA, 1981, 78: 996-1000.
[3] Bagaglio DM, Hait WN. Role of calmodulin-dependent phosphorylation of elongation-factor-2 in the proliferation of rat glial-cells [J]. Cell Growth Differ, 1994, 5: 1403-1408.
[4] Nilsson A, Nygard O. Phosphorylation of eukaryotic elongation factor 2 in differentiating and proliferating HL-60 cells [J]. Biochim Biophys Acta, 1995, 1268: 263-268.
[5] Parmer TG, Ward MD, Hait WN. Effects of rottlerin, an inhibitor of calmodulin-dependent protein kinase III, on cellular proliferation, viability, and cell cycle distribution in malignant glioma cells [J]. Cell Growth Differ, 1997, 8: 327-334.
[6] Parmer TG, Ward MD, Yurkow EJ, et al. Activity and regulation by growth factors of calmodulin dependent protein kinase III (elongation factor 2-kinase) in human breast cancer [J]. Br J Cancer, 1999, 79: 59-64.
[7] Wu H, Yang JM, Jin S, et al. Elongation factor-2 kinase regulates autophagy in human glioblastoma cells [J]. Cancer Res, 2006, 66: 3015-3023.
[8] Cheng Y, Li HJ, Ren XC, et al. Cytoprotective effect of the elongation factor-2 kinase-mediated autophagy in breast cancer cells subjected to growth factor inhibition [J]. PLoS One, 2010, 5: e9517.
[9] Zhang L, Zhang Y, Liu XY, et al. Expression of elongation factor-2 kinase contributes to anoikis resistance and invasion of human glioma cells [J]. Acta Pharmacol Sin, 2011, 32: 361-367.
[10] Ashour AA, Abdel-Aziz AA, Mansour AM, et al. Targeting elongation factor-2 kinase (eEF-2K) induces apoptosis in human pancreatic cancer cells [J]. Apoptosis, 2014, 19: 241-258.
[11] Redpath NT, Price NT, Proud CG. Cloning and expression of cDNA encoding protein synthesis elongation factor-2 kinase [J]. J Biol Chem, 1996, 271: 17547-17554.
[12] Ryazanov AG, Ward MD, Mendola CE, et al. Identification of a new class of protein kinases represented by eukaryotic elongation factor-2 kinase [J]. Proc Natl Acad Sci USA, 1997, 94: 4884-4889.
[13] Pigott CR, Mikolajek H, Moore CE, et al. Insights into the regulation of eukaryotic elongation factor 2 kinase and the interplay between its domains [J]. Biochem J, 2012, 442: 105-118.
[14] Mittl PR, Schneider-Brachert W. Sel1-like repeat proteins in signal transduction [J]. Cell Signal, 2007, 19: 20-31.
[15] Redpath NT, Proud CG. Purification and phosphorylation of elongation factor-2 kinase from rabbit reticulocytes [J]. Eur J Biochem, 1993, 212: 511-520.
[16] Clark K, Middelbeek J, Morrice NA, et al. Massive autophosphorylation of the Ser/Thr-rich domain controls protein kinase activity of TRPM6 and TRPM7 [J]. PLoS One, 2008, 3: e1876.
[17] Crawley SW, Gharaei MS, Ye Q, et al. Autophosphorylation activates dictyostelium myosin II heavy chain kinase A by providing a ligand for an allosteric binding site in the alpha-kinase domain [J]. J Biol Chem, 2011, 286: 2607-2616.
[18] Pyr Dit Ruys S, Wang X, Smith EM, et al. Identification of autophosphorylation sites in eukaryotic elongation factor-2 kinase [J]. Biochem J, 2012, 442: 681-692.
[19] Tavares CD, O'Brien JP, Abramczyk O, et al. Calcium/calmodulin stimulates the autophosphorylation of elongation factor 2 kinase on Thr-348 and Ser-500 to regulate its activity and calcium dependence [J]. Biochemistry, 2012, 51: 2232-2245.
[20] Mitsui K, Brady M, Palfrey HC, et al. Purification and characterization of calmodulin-dependent protein kinase III from rabbit reticulocytes and rat pancreas [J]. J Biol Chem, 1993, 268: 13422-13433.
[21] Diggle TA, Subkhankulova T, Lilley KS, et al. Phosphorylation of elongation factor-2 kinase on serine 499 by cAMP-dependent protein kinase induces Ca2+/calmodulin-independent activity [J]. Biochem J, 2001, 353: 621-626.
[22] Wang XM, Li W, Williams M, et al. Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase [J]. EMBO J, 2001, 20: 4370-4379.
[23] Knebel A, Morrice N, Cohen P. A novel method to identify protein kinase substrates: eEF2 kinase is phosphorylated and inhibited by SAPK4/p38 delta [J]. EMBO J, 2001, 20: 4360-4369.
[24] Smith EM, Proud CG. CDC2-cyclin B regulates eEF2 kinase activity in a cell cycle-and amino acid-dependent manner [J]. EMBO J, 2008, 27: 1005-1016.
[25] Redpath NT, Proud CG. Cyclic AMP-dependent protein kinase phosphorylates rabbit reticulocyte elongation factor-2 kinase and induces calcium-independent activity [J]. Biochem J, 1993, 293 (Pt 1): 31-34.
[26] Diggle TA, Redpath NT, Heesom KJ, et al. Regulation of protein-synthesis elongation-factor-2 kinase by cAMP in adipocytes [J]. Biochem J, 1998, 336: 525-529.
[27] Browne GJ, Finn SG, Proud CG. Stimulation of the AMP-activated protein kinase leads to activation of eukaryotic elongation factor 2 kinase and to its phosphorylation at a novel site, serine 398 [J]. J Biol Chem, 2004, 279: 12220-12231.
[28] Perraud AL, Zhao XY, Ryazanov AG, et al. The channel-kinase TRPM7 regulates phosphorylation of the translational factor eEF2 via eEF2-k [J]. Cell Signal, 2011, 23: 586-593.
[29] End D, Hanson M, Hashimoto S, et al. Inhibition of the phosphorylation of a 1000, 000-dalton soluble protein in whole cells and cell-free extracts of PC12 pheochromocytoma cells following treatment with nerve growth factor [J]. J Biol Chem, 1982, 257: 9223-9225.
[30] Brady MJ, Nairn AC, Wagner JA, et al. Nerve growth factor-induced down-regulation of calmodulin-dependent protein kinase-Ⅲ in PC12 cells involves cyclic AMP-dependent protein-kinase [J]. J Neurochem, 1990, 54: 1034-1039.
[31] Celis JE, Madsen P, Ryazanov AG. Increased phosphorylation of elongation factor 2 during mitosis in transformed human amnion cells correlates with a decreased rate of protein synthesis [J]. Proc Natl Acad Sci USA, 1990, 87: 4231-4235.
[32] Severinov KV, Melnikova EG, Ryazanov AG. Downregulation of the translation elongation factor 2 kinase in Xenopus laevis oocytes at the final stages of oogenesis [J]. New Biol, 1990, 2: 887-893.
[33] White-Gilbertson S, Kurtz DT, Voelkel-Johnson C. The role of protein synthesis in cell cycling and cancer [J]. Mol Oncol, 2009, 3: 402-408.
[34] Bagaglio DM, Cheng EH, Gorelick FS, et al. Phosphorylation of elongation factor 2 in normal and malignant rat glial cells [J]. Cancer Res, 1993, 53: 2260-2264.
[35] Proud CG. Signalling to translation: how signal transduction pathways control the protein synthetic machinery [J]. Biochem J, 2007, 403: 217-234.
[36] Roberts EC, Hammond K, Traish AM, et al. Identification of G2/M targets for the MAP kinase pathway by functional proteomics [J]. Proteomics, 2006, 6: 4541-4553.
[37] Carlberg U, Nilsson A, Skog S, et al. Increased activity of the eEF-2 specific, Ca2+ and calmodulin dependent protein kinase III during the S-phase in ehrlich ascites cells [J]. Biochem Biophys Res Commun, 1991, 180: 1372-1376.
[38] Arora S, Yang JM, Kinzy TG, et al. Identification and characterization of an inhibitor of eukaryotic elongation factor 2 kinase against human cancer cell lines [J]. Cancer Res, 2003, 63: 6894-6899.
[39] Tekedereli I, Alpay SN, Tavares CDJ, et al. Targeted silencing of elongation factor 2 kinase suppresses growth and sensitizes tumors to doxorubicin in an orthotopic model of breast cancer [J] PLoS One, 2012, 7: e41171.
[40] Leprivier G, Remke M, Rotblat B, et al. The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation [J]. Cell, 2013, 153: 1064-1079.
[41] Kenney JW, Moore CE, Wang X, et al. Eukaryotic elongation factor 2 kinase, an unusual enzyme with multiple roles [J]. Adv Biol Regul, 2014, 55: 15-27.
[42] White SJ, Kasman LM, Kelly MM, et al. Doxorubicin generates a proapoptotic phenotype by phosphorylation of elongation factor 2 [J]. Free Radic Biol Med, 2007, 43: 1313-1321.
[43] Cheng Y, Ren XC, Zhang Y, et al. Integrated regulation of autophagy and apoptosis by EEF2K controls cellular fate and modulates the efficacy of curcumin and velcade against tumor cells [J]. Autophagy, 2013, 9: 208-219.
[44] Yang YP, Liang ZQ, Gu ZL, et al. Molecular mechanism and regulation of autophagy [J]. Acta Pharm Sin (药学学报), 2005, 26: 1421-1434.
[45] Cheng Y, Ren XC, Zhang Y, et al. eEF-2 kinase dictates cross-talk between autophagy and apoptosis induced by Akt inhibition, thereby modulating cytotoxicity of novel Akt inhibitor MK-2206 [J]. Cancer Res, 2011, 71: 2654-2663.
[46] Hait WN, Wu H, Jin S, et al. Elongation factor-2 kinase: its role in protein synthesis and autophagy [J]. Autophagy, 2006, 2: 294-296.
[47] Py BF, Boyce M, Yuan J. A critical role of eEF-2K in mediating autophagy in response to multiple cellular stresses [J]. Autophagy, 2009, 5: 393-396.
[48] Ryazanov AG. Elongation factor-2 kinase and its newly discovered relatives [J]. FEBS Lett, 2002, 514: 26-29.
[49] Chen ZH, Gopalakrishnan SM, Bui MH, et al. 1-Benzyl-3-cetyl-2-methylimidazolium iodide (NH125) induces phosphorylation of eukaryotic elongation factor-2 (eEF2) a cautionary note on the anticancer mechanism of an eEF2 kinase inhibitor [J]. J Biol Chem, 2011, 286: 43951-43958.
[50] Xie CM, Liu XY, Sham KW, et al. Silencing of EEF2K (eukaryotic elongation factor-2 kinase) reveals AMPK-ULK1-dependent autophagy in colon cancer cells [J]. Autophagy, 2014, 10: 1495-1508.
[51] Pavur KS, Petrov AN, Ryazanov AG. Mapping the functional domains of elongation factor-2 kinase [J]. Biochemistry, 2000, 39: 12216-12224.
[52] Yang J, Yang JM, Iannone M, et al. Disruption of the EF-2 kinase/Hsp90 protein complex: a possible mechanism to inhibit glioblastoma by geldanamycin [J]. Cancer Res, 2001, 61: 4010-4016.
[53] Cho SI, Koketsu I, Ishihara H, et al. Novel compounds, ‘1, 3-selenazine derivatives’ as specific inhibitors of eukaryotic elongation factor-2 kinase [J]. Biochim Biophys Acta, 2000, 1475: 207-215.
[54] Hori H, Nagasawa H, Ishibashi M, et al. TX-1123: An antitumor 2-hydroxyarylidene-4-cyclopentene-1, 3-dione as a protein tyrosine kinase inhibitor having low mitochondrial toxicity [J]. Bioorg Med Chem, 2002, 10: 3257-3265.
[55] Lockman JW, Reeder MD, Suzuki K, et al. Inhibition of eEF2-K by thieno[2, 3-b]pyridine analogues [J]. Bioorg Med Chem Lett, 2010, 20: 2283-2286.
[56] Devkota AK, Tavares CDJ, Warthaka M, et al. Investigating the kinetic mechanism of inhibition of elongation factor 2 kinase by NH125: evidence of a common in vitro artifact [J]. Biochemistry, 2012, 51: 2100-2112.
[57] Edupuganti R, Wang Q, Tavares CD, et al. Synthesis and biological evaluation of pyrido[2, 3-d]pyrimidine-2, 4-dione derivatives as eEF-2K inhibitors [J]. Bioorg Med Chem, 2014, 22: 4910-4916.
[58] Ryazanov AG, Hait WN, Pavur KS. Elongation factor-2 kinase (EF-2 kinase), and methods of use therefor: US, 6346406 [P]. 2002-12-02.Devkota AK, Warthaka M, Edupuganti R, et al. High-throughput screens for eEF-2 kinase [J]. J Biomol Screen, 2014, 19: 445-452.
相关文献:
1.任景, 严碧波, 石峰, 熊兵, 沈竞康.HSP90小分子抑制剂研究进展[J]. 药学学报, 2015,50(6): 640-649
2.牛非, 李燕, 来芳芳, 陈晓光.低氧诱导因子1抑制剂的抗肿瘤研究进展[J]. 药学学报, 2014,49(6): 832-836
3.来芳芳, 刘晓宇, 牛非, 郎立伟, 谢平, 陈晓光.新型HIF-1抑制剂三白脂素-8衍生物LXY6099的抗肿瘤作用[J]. 药学学报, 2014,49(5): 622-626
4.董丹丹, 肖燕燕, 刘 伟, 周红刚, 杨 诚.Aurora-B激酶及其抑制剂研究进展[J]. 药学学报, 2013,48(4): 457-465
5.何裕军, 刘瑞环, 宁澄清, 余聂芳.多腺苷二磷酸核糖聚合酶抑制剂抗肿瘤的研究进展[J]. 药学学报, 2013,48(5): 655-660
6.张彩霞,何红伟,邵荣光.鞘氨醇激酶与肿瘤[J]. 药学学报, 2013,48(7): 971-978
7.阮秀琴, 陈 明, 吴梧桐, 尤启冬.四氢咔啉类纺锤体驱动蛋白抑制剂的合成和抗肿瘤活性研究[J]. 药学学报, 2013,48(7): 1119-1123
8.李良, 刘红, 张胜华, 胡磊, 甄永苏.肉桂酰胺格尔德霉素的体内外抗肿瘤活性[J]. 药学学报, 2013,48(12): 1771-1777
9.周洁, 朱枝祥, 陈晓光, 徐柏玲.氮杂吲哚类PARP-1抑制剂的合成及活性评价[J]. 药学学报, 2013,48(12): 1792-1799
10.郭佳, 李凤然, 刘洋, 程卯生.碳酸酐酶IX小分子抑制剂的研究进展[J]. 药学学报, 2013,48(11): 1637-1643
11.尚 海 潘 莉 杨 澍 陈 虹 程卯生.微管蛋白抑制剂的研究进展[J]. 药学学报, 2010,45(9): 1078-1088
12.李香艳,陈晓光.蛋白激酶Cβ与肿瘤的关系及其抑制剂Enzastaurin的研究进展[J]. 药学学报, 2009,44(5): 449-455
13.李景 张大永 吴晓明.泛素-蛋白酶体及其抑制剂的分类与合成[J]. 药学学报, 2009,44(12): 1313-1319
14.吴文, 卢骋, 陈思宇, 余聂芳.已上市和部分正在Ⅲ期临床开发中的多靶点激酶抑制剂抑酶谱及信号传导通路分析[J]. 药学学报, 2009,44(3): 242-257
15.曹 鑫 尤启冬 李志裕 郭青龙 杨 勇 尚 靖 严 明 陈基旺 陈梦伶.具有Src激酶和NO合酶双重抑制作用的4-芳杂胺-3-氰基喹啉类抗肿瘤化合物的设计、合成与生物活性研究[J]. 药学学报, 2009,44(3): 288-295
16.季宇彬;周建华;左明新;尤启冬.新型Topo I抑制剂CPUY013对胃腺癌细胞BGC823的体内外作用[J]. 药学学报, 2008,43(8): 811-818
17.阮秀琴;尤启冬;杨蕾;吴梧桐.β-四氢咔啉衍生物的合成和生物活性[J]. 药学学报, 2008,43(8): 828-832
18.徐岩;王广树;孙薇;杨晓虹;徐利保.小分子IGF-1R抑制剂的研究进展[J]. 药学学报, 2008,43(10): 979-984
19.张崇敬;张志辉;徐柏玲;王玉玲.Pin1及其抑制剂的研究进展[J]. 药学学报, 2008,43(1): 9-9
20.茆勇军;李海泓;李剑峰;沈敬山.蛋白酪氨酸激酶信号转导途径与抗肿瘤药物[J]. 药学学报, 2008,43(4): 323-334
21.张胜华;粟俭;甄永苏;.丹酚酸A抑制核苷转运并增强化疗药物的抗肿瘤作用丹酚酸A抑制核苷转运并增强化疗药物的抗肿瘤作用[J]. 药学学报, 2004,39(7): 496-499
22.毛立民;于世凤;孙开华.金属蛋白酶抑制剂BB-94抑制Lewis肺癌生长和转移的实验研究[J]. 药学学报, 2000,35(6): 473-475
23.王瑞虹;张鸿卿;方敏;薛绍白.蛋白激酶抑制剂staurosporine增强抗癌药对肿瘤细胞的杀伤[J]. 药学学报, 1996,31(6): 411-415
24.粟俭;甄永苏;戚长菁;陈文君.真菌产生的新核苷转运抑制剂增强药物的抗肿瘤活性[J]. 药学学报, 1994,29(9): 656-661